Simulation of Arrhythmogenic Effect of Rogue RyRs in Failing Heart by Using a Coupled Model

<table>Triggered action potential in failing myocyte when <svg height="18.3125" id="M218" style="vertical-align:-5.73166pt" version="1.1" viewbox="0 0 42.875 18.3125" width="42.875" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,0,0,-.017,.062,11.113)"><path d="M857 650l-6 -28q-44 -4 -61.5 -16.5t-29.5 -48.5q-11 -32 -37 -166l-78 -399h-29l-351 537h-4l-56 -276q-24 -120 -24 -164q0 -35 17.5 -46t75.5 -15l-6 -28h-245l7 28q41 2 62 14t31 44q10 30 41 171l53 245q8 44 6.5 60.5t-14.5 33.5q-10 15 -27 19.5t-64 6.5l6 28h153
l350 -516h5l48 257q25 131 25 171q0 34 -17.5 45t-77.5 15l7 28h240z" id="x1D441"></path></g>
<g transform="matrix(.012,0,0,-.012,14.925,15.188)"><path d="M181 342h2q63 107 121 107q24 0 41 -16t17 -34q0 -34 -32 -49q-17 -7 -26 2q-21 20 -43 20q-20 0 -42 -22t-38 -63v-183q0 -50 12.5 -62t69.5 -16v-26h-230v26q47 5 58 17t11 61v207q0 49 -9 60.5t-53 16.5v23q74 12 141 40v-109z" id="x72"></path></g><g transform="matrix(.012,0,0,-.012,19.185,15.188)"><path d="M257 449q92 0 154 -65t62 -158q0 -112 -67 -175t-150 -63q-98 0 -158.5 66.5t-60.5 154.5q0 59 21 106.5t54.5 75.5t71 43t73.5 15zM244 416q-48 0 -81 -47t-33 -128q0 -96 38 -158t99 -62q51 0 82 43.5t31 139.5q0 91 -36 151.5t-100 60.5z" id="x6F"></path></g><g transform="matrix(.012,0,0,-.012,25.253,15.188)"><path d="M463 437l5 -8q-21 -38 -45 -51l-57 3q30 -35 30 -88q0 -76 -52.5 -118t-122.5 -42q-24 0 -51 5q-30 -21 -30 -42q0 -16 16 -27t47 -11q19 0 54 0.5t52 0.5q36 0 65.5 -8t53.5 -36t24 -74q0 -77 -75 -137.5t-174 -60.5q-79 0 -126 37.5t-48 84.5q0 32 24 56q21 21 83 70
q-49 15 -74 55q-13 20 -11 42q56 21 88 61q-37 16 -62.5 51t-25.5 83q0 78 56.5 122t122.5 44h1q51 0 96 -27q71 4 136 15zM219 418q-34 0 -58 -32t-24 -87q0 -59 26.5 -96.5t67.5 -37.5q35 1 59 32t24 87q0 59 -26 96.5t-69 37.5zM241 -11q-62 0 -87 -21q-46 -39 -46 -78
q0 -41 38 -68.5t94 -27.5q69 0 106.5 31t37.5 80q0 52 -45 71q-33 13 -98 13z" id="x67"></path></g><g transform="matrix(.012,0,0,-.012,30.822,15.188)"><path d="M518 50v-26q-32 -4 -77 -16l-37 -11t-33 -9l-6 6v71q-56 -42 -74 -52q-43 -25 -77 -25q-55 0 -89.5 36.5t-34.5 112.5v196q0 38 -6.5 48.5t-26.5 15.5l-28 6v23q19 1 72 7q59 9 71 11q-3 -31 -3 -145v-135q0 -113 88 -113q59 0 108 48v234q0 38 -8 49t-34 15l-36 6v23
q44 2 90 8q37 4 67 10v-334q0 -37 8.5 -47t38.5 -12z" id="x75"></path></g><g transform="matrix(.012,0,0,-.012,37.14,15.188)"><path d="M380 106l15 -22q-42 -52 -87 -74t-76 -22q-89 0 -142 62t-53 151q0 103 66 175q67 73 146 73h1q61 0 105.5 -46.5t44.5 -105.5q0 -16 -4.5 -22.5t-18.5 -9.5q-54 -10 -262 -17q1 -95 46 -143.5t104 -48.5q61 0 115 50zM225 412q-35 0 -64.5 -32.5t-40.5 -90.5q83 0 170 3
q14 0 19 4.5t5 15.5q1 41 -23.5 70.5t-65.5 29.5z" id="x65"></path></g>
</svg> = 1.75 rogue RyR/<svg height="12.175" id="M219" style="vertical-align:-3.56265pt" version="1.1" viewbox="0 0 9.5625 12.175" width="9.5625" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,0,0,-.017,.062,7.675)"><path d="M538 96q-38 -45 -84 -76.5t-71 -31.5q-44 0 -15 117q12 49 18 89h-2q-99 -128 -163 -178q-36 -28 -70 -28q-26 0 -44 38h-2q-16 -69 -16 -129q0 -43 11 -75.5t24 -42.5l1 -6q-7 -12 -24.5 -23t-37.5 -11q-40 0 -40 76q0 52 35 202l94 407l78 24l5 -5q-32 -122 -72 -310
q-7 -33 0 -55t25 -22q36 0 105.5 75t107.5 145l32 146l75 26h10q-50 -197 -78 -347q-7 -38 6 -38q7 0 31 17t47 39z" id="x1D707"></path></g>
</svg>m<sup>2</sup>. Five figures from top to bottom represent membrane potential, cytoplasmic <svg height="20.0625" id="M220" style="vertical-align:-3.3907pt" version="1.1" viewbox="0 0 47.8125 20.0625" width="47.8125" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,0,0,-.017,.062,15.775)"><path d="M290 -163h-170v866h170v-28q-79 -7 -94 -19.5t-15 -72.5v-627q0 -59 14.5 -71.5t94.5 -19.5v-28z" id="x5B"></path></g><g transform="matrix(.017,0,0,-.017,5.927,15.775)"><path d="M614 175l29 -10q-33 -109 -57 -154q-121 -26 -184 -26q-90 0 -160.5 29t-112.5 77t-63.5 105.5t-21.5 119.5q0 157 108 253t277 96q36 0 71.5 -5t69 -13.5t36.5 -8.5q15 -102 20 -150l-29 -8q-20 79 -66.5 114t-128.5 35q-119 0 -187.5 -86t-68.5 -207
q0 -140 73.5 -227.5t188.5 -87.5q73 0 119.5 37.5t86.5 116.5z" id="x43"></path></g><g transform="matrix(.017,0,0,-.017,17.231,15.775)"><path d="M433 39l-85 -51q-27 0 -47 20q-16 16 -24 44q-5 -3 -24 -16.5t-27 -18.5t-23 -13.5t-25 -12t-19 -3.5q-52 0 -86 36.5t-34 85.5q0 71 81 99q128 43 155 65v17q0 54 -23 83.5t-62 29.5q-28 0 -45 -19t-29 -66q-7 -23 -29 -23q-15 0 -29 13t-14 30t31 40q25 19 68.5 40.5
t81.5 29.5q49 0 82 -27q45 -39 45 -123v-185q0 -60 35 -60q18 0 36 11zM275 84v156q-12 -6 -49 -23t-41 -19q-31 -14 -46 -31t-15 -43q0 -35 22.5 -55.5t48.5 -20.5q19 0 42 10.5t38 25.5z" id="x61"></path></g>
<g transform="matrix(.012,0,0,-.012,24.688,7.613)"><path d="M412 140l28 -9q0 -2 -35 -131h-373v23q112 112 161 170q59 70 92 127t33 115q0 63 -31 98t-86 35q-75 0 -137 -93l-22 20l57 81q55 59 135 59q69 0 118.5 -46.5t49.5 -122.5q0 -62 -29.5 -114t-102.5 -130l-141 -149h186q42 0 58.5 10.5t38.5 56.5z" id="x32"></path></g><g transform="matrix(.012,0,0,-.012,30.399,7.613)"><path d="M535 230h-212v-233h-58v233h-213v50h213v210h58v-210h212v-50z" id="x2B"></path></g>
<g transform="matrix(.017,0,0,-.017,38.013,15.775)"><path d="M226 -163h-170v27q79 7 94 20t15 73v627q0 59 -15 72t-94 20v27h170v-866z" id="x5D"></path></g>
<g transform="matrix(.012,0,0,-.012,43.875,19.863)"><path d="M244 607q0 -25 -15.5 -43t-37.5 -18q-19 0 -32 13t-13 35q0 21 15 41t39 20q20 0 32 -14t12 -34zM222 91q-29 -33 -79 -68t-75 -35q-13 0 -19 7.5t-6 31t10 65.5l62 253q5 26 -1 26q-21 0 -72 -43l-13 24q43 40 91 68t71 28q30 0 10 -78l-71 -274q-8 -30 3 -30
q16 0 76 48z" id="x1D456"></path></g>
</svg>, SR luminal [Ca<sup>2+</sup>]<sub>SR</sub>, <svg height="15.4375" id="M221" style="vertical-align:-3.41936pt" version="1.1" viewbox="0 0 35.174999 15.4375" width="35.174999" xmlns="http://www.w3.org/2000/svg" xmlns:xlink="http://www.w3.org/1999/xlink">
<g transform="matrix(.017,0,0,-.017,.062,11.113)"><path d="M414 650l-6 -28q-63 -4 -78.5 -17.5t-27.5 -71.5l-77 -416q-11 -58 0.5 -71.5t77.5 -17.5l-5 -28h-275l8 28q63 4 79.5 18.5t27.5 70.5l80 416q11 57 -2 71t-81 18l6 28h273z" id="x1D43C"></path></g>
<g transform="matrix(.012,0,0,-.012,7.487,15.188)"><path d="M719 650v-28q-43 -2 -62 -15t-22 -44q-6 -47 -6 -169v-403h-31l-426 524h-2v-251q0 -111 6 -169q4 -37 24 -50.5t72 -16.5v-28h-237v28q45 2 64.5 16t23.5 49q6 62 6 171v220q0 54 -3 68.5t-17 32.5q-16 19 -34.5 26.5t-54.5 10.5v28h147l418 -502h3v246q0 117 -7 166
q-4 34 -24.5 47t-73.5 15v28h236z" id="x4E"></path></g><g transform="matrix(.012,0,0,-.012,16.031,15.188)"><path d="M433 39l-85 -51q-27 0 -47 20q-16 16 -24 44q-5 -3 -24 -16.5t-27 -18.5t-23 -13.5t-25 -12t-19 -3.5q-52 0 -86 36.5t-34 85.5q0 71 81 99q128 43 155 65v17q0 54 -23 83.5t-62 29.5q-28 0 -45 -19t-29 -66q-7 -23 -29 -23q-15 0 -29 13t-14 30t31 40q25 19 68.5 40.5
t81.5 29.5q49 0 82 -27q45 -39 45 -123v-185q0 -60 35 -60q18 0 36 11zM275 84v156q-12 -6 -49 -23t-41 -19q-31 -14 -46 -31t-15 -43q0 -35 22.5 -55.5t48.5 -20.5q19 0 42 10.5t38 25.5z" id="x61"></path></g><g transform="matrix(.012,0,0,-.012,21.254,15.188)"><path d="M614 175l29 -10q-33 -109 -57 -154q-121 -26 -184 -26q-90 0 -160.5 29t-112.5 77t-63.5 105.5t-21.5 119.5q0 157 108 253t277 96q36 0 71.5 -5t69 -13.5t36.5 -8.5q15 -102 20 -150l-29 -8q-20 79 -66.5 114t-128.5 35q-119 0 -187.5 -86t-68.5 -207
q0 -140 73.5 -227.5t188.5 -87.5q73 0 119.5 37.5t86.5 116.5z" id="x43"></path></g><g transform="matrix(.012,0,0,-.012,29.262,15.188)"><path d="M433 39l-85 -51q-27 0 -47 20q-16 16 -24 44q-5 -3 -24 -16.5t-27 -18.5t-23 -13.5t-25 -12t-19 -3.5q-52 0 -86 36.5t-34 85.5q0 71 81 99q128 43 155 65v17q0 54 -23 83.5t-62 29.5q-28 0 -45 -19t-29 -66q-7 -23 -29 -23q-15 0 -29 13t-14 30t31 40q25 19 68.5 40.5
t81.5 29.5q49 0 82 -27q45 -39 45 -123v-185q0 -60 35 -60q18 0 36 11zM275 84v156q-12 -6 -49 -23t-41 -19q-31 -14 -46 -31t-15 -43q0 -35 22.5 -55.5t48.5 -20.5q19 0 42 10.5t38 25.5z" id="x61"></path></g>
</svg>, and line-scan image along longitudinal direction of the myocyte, respectively, in failing ventricular cell.</table>

Computational and Mathematical Methods in Medicine

fig5

Figure 5

Figure 5: Simulation of Arrhythmogenic Effect of Rogue RyRs in Failing Heart by Using a Coupled Model 